The effect of epigenetic regulation of fucosylation on TRAIL-induced apoptosis

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many cancer cells but not in normal ones. Recombinant TRAIL and agonistic antibodies to its cognate receptors are currently being studied as promising anticancer drugs. However, preclinical and clinical studies have shown that many types of human cancers are resistant to TRAIL agonists. We previously reported that a deficiency of fucosylation, which is one of the most common oligosaccharide modifications, leads to resistance to TRAIL-induced apoptosis. In contrast, DNA methylation is associated with silencing of various tumor suppressor genes and resistance of cancer cells to anticancer drugs. The aim of this study is to clarify the involvement of DNA methylation in the regulation of cellular fucosylation and the susceptibility to TRAIL-induced apoptosis. When nineteen cancer cell lines with relatively low fucosylation levels were treated with a novel methyltransferase inhibitor, zebularine, an increase in the fucosylation level was observed in many cancer cell lines. The expression of fucosylation-related genes, such as the FX, GDP-fucose transporter, and Fut4 genes, was significantly increased after the treatment with zebularine. Moreover, a synergistic effect of zebularine on TRAIL-induced apoptosis was observed in several cancer cell lines, in which fucosylation was increased by treatment with zebularine. This synergistic effect was independent of the expression of TRAIL receptors and caspase-8. These results indicate that cellular fucosylation is regulated through DNA methylation in many cancer cells. Moreover, zebularine might be useful as a combination drug with TRAIL-based therapies in patients with TRAIL-resistant cancer.